The Peachey lab is focused on the outer retina, to understand the biology that underlies the initial stages of the visual process and to identify genetic mutations associated with visual disorders. The first research area combines the power of mouse genetics with electrophysiological, anatomical and biochemical assays. Transgenic, systemic knockout and conditional knockout models allow the expression of a target to be manipulated and the effect of that manipulation evaluated. Some projects conducted during the most recent RCS award (2015-date) are highlighted here: (A) To better understand the rod and cone visual cycles by which photoreceptors regain sensitivity following bright light exposure the CDA-2 program of Philip Kiser utilizes pharmacological blockade of known visual cycle components (e.g., RPE65) in mouse mutants lacking proteins such as DES1 that have been proposed as playing key roles. (B) To clarify the metabolic processes that support photoreceptor function, a recent VA Merit Review supported studies of mice lacking the ability to transport glucose (by targeting GLUT1) or lactate (by targeting basigin) across cell membranes of rods, cones and the retinal pigment epithelium (RPE). (C) To understand the role of retinoschisin (RS1) we worked with a panel of Rs1 mutants to clarify the disease phenotype. Based on the severe phenotype, a new R01 focuses on the earliest stages of development in the mouse models and uses psychophysical assays to determine whether RS1 mutations result in incomplete photoreceptor development. (D) Forward genetics is used to develop new mouse models for vision research, in work supported by a subcontract to Jackson Laboratory. We collaborate through design of ocular screens, gene mapping and defining the retinal phenotype. To date, this collaboration has developed >20 mutants involving almost as many genes. Notably this collaboration has led to the identification of two human disease genes, including CTNNA1 during the most recent RCS award. The Peachey lab has a long-standing interest in defining the genetic risk profile for age-related macular degeneration (AMD). This began as a Merit Review in the early 2000?s focused on candidate genes, an effort that developed into our serving as a site within the International Age-Related Macular Degeneration Genetics Consortium (IAMDGC). During the most recent RCS award, the IAMDGC published the most comprehensive assessment of AMD genetics to date. With the advent of the VA Million Veteran Program (MVP), during the most recent RCS award we submitted a successful application to conduct the first multi-ethnic analysis of AMD genetics. After defining an accurate ICD- code based algorithm to identify AMD Cases and Controls without AMD, in the absence of gold-standard ocular imaging results, we conducted genome wide association studies (GWAS) in MVP for European- American (EA), African-American (AA) and Hispanic-American (HA) Veterans. The EA GWAS replicated and extended the IAMDGC results. When coupled with IAMDGC data and analysis of other databases, we identified a number of new AMD risk loci. Perhaps more important, we noted marked differences in the AMD risk profiles of EA as compared to AA and HA Veterans. A newly funded Merit Review will extend this successful approach to conduct additional genetic studies of ocular conditions that are relevant to the Veterans Health Administration based on their prevalence. In each case, we will validate a Case-Control algorithm and then move to a trans-ethnic genetic analysis. For some conditions, we will conduct the first analysis that compares genetic risk across ethnic groups. For other conditions, this will be the first genetic analysis ever conducted. A better understanding of ocular diseases such as AMD, glaucoma, cataract, or diabetic retinopathy is an important step towards treatments to slow/halt disease progression, and possibly reduce healthcare costs.